The present invention relates to a biologically active composition from which one or more biologically active components are to be released. More specifically, the invention relates to a biologically active composition wherein the biologically active agent is present in a supersaturated state within a carrier without being precipitated therefrom.
From inter alia toxicological points of view, it is often preferred, upon treatment of diseases or symptoms thereof, to deliver drugs directly to their site(s) of action. It is well known that the risks of obtaining detrimental effects of systemic origin are often markedly reduced if a drug is delivered directly to its site(s) of action. Furthermore, systemic delivery often involves metabolism of the drug prior to its appearance at the site of action, which leads to a subsequent reduction of its biological effect. Another important aspect is that in e.g. cases of imminent overdosage, allergic reactions or administration of contraindicating drugs, it is easy to remove topical compositions in contrast to drugs administered per-orally or by injection.
As used herein, topical administration comprises inter alia dermal, sub-lingual, gingival, buccal, transdermal, nasal, vaginal and rectal administration, whereby the resulting biological effect may be local and/or systemic.
In e.g. dermal, nasal, vaginal, buccal or sub-lingual administration, only a very limited number of drugs are capable of permeating into the human body by themselves at a useful rate. Consequently, a lot of research has been conducted in order to investigate the possibility of both improving traditional non-invasive delivery techniques and developing novel non-invasive drug delivery systems or devices intended for systemic and/or internal use. Three fundamentally different approaches towards this objective have been disclosed.
Firstly, there is the well known possibility of improving the penetration properties of the drug by chemical modification thereof. After the drug has entered the body, its pharmacologically active form is obtained by chemical reaction(s) in vivo. However, this so called pro-drug approach is only occasionally a succesful alternative. There are several reasons therefor, such as i) the penetration rate of the pro-drug may still be too low, ii) the pro-drug may be toxic or otherwise harmful, or iii) the in vivo conversion to the active form of the drug is too slow and/or partially results in inactive or toxic compounds. A distantly related approach is the preparation of an ion pair between a drug and an appropriate counter ion. However, generally such an ion pair does not display any markedly improved penetration rate through human barriers.
Secondly, the properties of the barrier may be changed in order to facilitate the drug delivery. Methods of achieving this are e.g. ultra-sonication, applying of electrical current or the use of so called penetration enhancers in the composition. All of these methods act by disrupting the structure of the barrier, thereby facilitating drug diffusion through the barrier into the body, and/or improving the drug solubility in the barrier. However, the methods involving e.g. heat, ultra-sonication and electrical current are generally not designed for being easily managed by the patient in a convenient manner, and therefore require hospitalisation, which is a major disadvantage with said methods. In addition, all methods which are based on the approach of changing the barrier properties are questionable from a toxicological point of view due to the observations that i) adverse effects on the cells of the barrier have been demonstrated, and ii) a reduction of the protective properties of the barrier also result in increased penetration rate for any substance, not only the drug, that is present at the site of administration. It should also be mentioned, that a majority of the known chemical penetration enhancers require some time for the onset of their action, i.e. display a lag time of action, since they must be established in the barrier before the actual increase in penetration rate is observed.
Thirdly, the driving force of the drug for entering the body can be changed. That is, the difference in the electrochemical potential of the drug between the drug reservoir and the body can be increased. Drug delivery systems based on this approach result in a high flux of the drug through the barrier and usually also display a reduced lag time of action.
In methods based on iontophoresis, this approach is utilised by applying an electrical potential gradient across the barrier obviously, these methods are mainly suitable for drugs having a net charge and are therefore much less efficient for uncharged and zwitterionic species, since the flux of the two latter species is improved mainly due to e.g. osmotic and electroosmotic driving forces. Iontophoresis methods also have the disadvantage that they may alter the structure of the barrier.
In another approach, the flux of a drug into the body can be enhanced by increasing the chemical potential of the drug in the carrier therefor. This is normally performed by chemical optimisation of the drug composition by adjusting the degree of saturation of the drug in said carrier. The methods based on this approach offer several advantages as compared to the previously mentioned methods, since the flux of the drug is increased in comparison with subsaturated and saturated systems. Furthermore, the properties of the barrier itself are comparatively less affected and the lag time of initiation for the pharmacological effect is reduced. There are two particularly important aspects in this approach:
i) creation of an initial high chemical potential of the drug in the composition
ii) maintenance of a high chemical potential of the drug in the vicinity of the barrier after the application of the composition.
Therefore, it is usually desirable to prepare pharmaceutical compositions which are saturated with respect of the drug. During application, another important aspect of said composition is that the solubility and diffusion properties of the drug in the used vechicle must preclude depletion of the drug in the vicinity of the barrier. Examples of compositions used for this purpose are microemulsions and emulsions.
Another approach towards keeping the composition saturated is the use of an excess amount of drug (non-solubilised) in the carrier, whereby the drug is subsequently dissolved as it replaces the drug which has penetrated through the barrier.
Yet another approach is the use of a supersaturated composition of the drug. Here, the driving force of the drug to penetrate the barrier is higher than in the saturated composition, since the drug in a supersaturated composition has higher chemical potential in comparison with the corresponding saturated composition. For example, such compositions have been prepared according to the following means or principles: i) dissolving the drug at temperatures and/or pressures at which the solubility of the drug is higher as compared to those temperatures and/or pressures that are relevant for medication (W. L. Chou and S. Riegelmann, J. Pharm. Sci., Vol.60, No.9, pp.1281-1302, 1971; WO 97/10812), ii) using solid dispersions or eutectic mixtures or solid drug particles of low degree of crystallinity or of high energy polymorphs (W. L. Chou and S. Riegelmann, supra), iii) mixing a saturated drug solution with a non-solvent therefor, thereby performing a merely physical operation, in situ or prior to application, with or without the presence of an antinucleating agent (U.S. Pat. No. 4,940,701; U.S. Pat. No. 4,767,751), iv) solvent evaporation to the surrounding air (Coldman et al., J. Pharm. Sci., 58, No.9 (1969), pp 1098-1102), v) solvent penetration into the human body, vi) water uptake into the composition from the human body, vii) pH-changes in the composition caused by H+-uptake from the human body, or viii) dispersing an aqueous solution or emulsion of a drug in an aqueous dispersion of a polymer latex (Lichtenberger et al., xe2x80x9cPolymer films from aqueous polymer dispersions as carriers for transdermal delivery of lipophilic drugsxe2x80x9d, 15th Int Symp CRS:Basel 1988; Abstr 89). An important common denominator of iv)-vii) is that the supersaturation is not initally present in the composition, and is therefore de facto not accomplished until the composition is applied to a human body. Furthermore, a major problem with all the compositions i)-viii) is that the drug generally precipitates in a relatively short time, in which case the saturation degree becomes markedly reduced.
DD 217 989 discloses a supersaturated composition, wherein the carrier matrix is an acrylate (scopacryl d), optionally in combination with an excipient, which matrix is claimed to prevent recrystallisation of a supersaturated drug present therein:
W. L. Chou and S. Riegelmann (J. Pharm. Sci., Vol.58, No. 12, pp.1505-1510, 1969) have reported that in matrices of higher molecular weight polyethylene glycols, precipitation of a supersaturated drug dissolved therein is usually sluggish.
Other prior art of interest is WO 97/10812, which discloses a method for preparing supersaturated systems by controlled melting of an admixture of a drug and a polymeric carrier material.
Mention can also be made of GB 2 306 885, which discloses a composition, where a supersaturated state is attained in an aqueous carrier matrix.
As prior art, reference is also made to WO 97/00670, which discloses a composition based on ingredients similar to those utilized in the present invention. However, said reference does not disclose or suggest any supersaturated state or even less those features of the present invention which have been found crucial to impart a stable, supersaturated state to such a composition.
In summary, none of the above prior art discloses or suggests the essential features of the supersaturated composition according to the present invention.
The inventors have now found a novel approach for obtaining a biologically active composition which provides both unexpected stability and high delivery rate to a supersaturated active component present therein. According to the disclosed invention, a biologically active agent is present in a substantially stable supersaturated state within a carrier therefor.
Briefly, it has been found that by subjecting carrier starting substance(s) to such chemical reaction(s) that a carrier matrix of substantially non-crystalline, or amorphous, nature is created, the carrier matrix thus obtained has the property to inter alia maintain a biologically active agent in a surprisingly stable supersaturated state. In a biologically active composition thus prepared, the precipitation of said agent is substantially, or completely, inhibited by said carrier matrix per se.
The term xe2x80x9cbiologically active agentxe2x80x9d, as used herein, also comprises such progenitors thereto which are readily transformable, e.g. enzymatically and/or hydrolytically, to a biologically active agent per se.
Thus, the present invention relates to a novel biologically active composition which comprises a biologically active agent to be released therefrom, said biologically active agent being dissolved and/or dispersed in a supersaturated state within a carrier, which carrier is a liquid and/or solid substantially non-crystalline matrix, and where the precipitation of said biologically active agent is substantially, or completely, inhibited therein.
The term xe2x80x9cliquidxe2x80x9d as used in connection with the present invention should be interpreted in a broad sense, viz as any material being a mobile or viscous liquid, rubber, glass or plastic; thus including solutions, creams, pastes, ointments and gels within the scope of the claims.
The present invention also relates to a method for the preparation of a biologically active composition comprising a biologically active agent dissolved and/or dispersed in a supersaturated state in a carrier therefor as well as to said composition for use as a medicament.
The term xe2x80x9cpharmaceutically active agentxe2x80x9d, as used herein, also comprises such progenitors, e.g. pro-drugs, which are readily transformable, e.g. enzymatically and/or hydrolytically, to a pharmaceutically active agent per se.
One of the objects of the present invention is thus to provide a supersaturated composition which does not display any significant precipitation or loss of effect during long-term storage at room temperature, or even at above or below room temperature, during e.g. months or even years.
Another object of the present invention is to provide a supersaturated composition which does not display any significant precipitation or loss of effect during its application to a human or animal patient.
Still another object of the present invention is to provide a carrier matrix which is suitable in preparation of a composition having a particularly high degree of supersaturation of a drug (vide infra).
A further object of the present invention is to provide a carrier matrix which is particularly suitable for attaining supersaturation of biologically active agents which are sensitive towards hydrolysis in carrier matrices based on water or otherwise are chemically and/or physically unstable.
Yet another object of the present invention is to provide a stable supersaturated composition which is easily handled and does not require professional assistance upon use thereof.
As a result of the high delivery rate of its active component (s), yet another object of the present invention is to provide a composition which allows for efficient topical treatment, preferably dermal or transdermal administration to small areas, which is a general advantage in the topical administration of drugs.